| The cardiovascular and respiratory systems are well integrated to evoke closely coordinated responses from both systems. For example, heart rate increases during inspiration and decreases during expiration, which is referred to as respiratory sinus arrhythmia, and ensures the proper diffusion for oxygen within the lungs. Heart rate is dominated by the activity of parasympathetic cardiac vagal neurons descending from the nucleus ambiguus. The activity of cardiac vagal neurons is closely matched to respiration; respiratory sinus arrhythmia is mediated by inhibitory GABAergic and glycinergic neurotransmission to cardiac vagal neurons during inspiration. Excitatory neurotransmission is not altered under resting respiration. The strongest cardiorespiratory responses, however, are evoked by challenges such as hypoxia. Hypoxia simultaneously transforms eupnea to gasping and evokes a parasympathetically mediated bradycardia. Intermittent episodes of hypoxia elicit network changes distinct from single hypoxic episodes, characterized by long term facilitation of respiratory activity. However, the mechanisms mediating central cardiorespiratory network interactions during episodic and continuous hypoxia are unknown. To examine central cardiorespiratory responses to episodic hypoxia, we used in vitro medullary slices that allow simultaneous examination of rhythmic respiratory-related activity and synaptic neurotransmission to cardioinhibitory vagal neurons. We show that whereas continuous hypoxia does not stimulate excitatory neurotransmission to cardioinhibitory vagal neurons, acute intermittent hypoxia of equivalent duration incrementally recruits respiratory-evoked excitatory neurotransmission to cardioinhibitory vagal neurons. This recruitment is dependent reactive oxygen species generation. Further, we demonstrate that reactive oxygen species are incrementally generated in glutamatergic neurons in the ventrolateral medulla during intermittent hypoxia. In addition, while a single continuous hypoxic administration does not alter glutamatergic neurotransmission to cardiac vagal neurons, upon recovery from hypoxia cardiac vagal neurons receive respiratory related glutamatergic synaptic inputs. The enhancement of excitatory neurotransmission to cardiac vagal neurons upon recovery from hypoxia is mediated by activation of purinergic P2X receptors. The results from this study demonstrate differential responses to intermittent and continuous hypoxia within the central cardiorespiratory network. Further, these results suggest a neurochemical basis for the pronounced bradycardia that protects the heart against injury during intermittent hypoxia, and implicate enhanced glutamatergic neurotransmission to cardiac vagal neurons in cardiorespiratory diseases such as obstructive sleep apnea. |
